LEP and obesity due to melanocortin 4 receptor deficiency: Notably, obesity-induced systemic alterations include impaired nutritional parameters (e.g., blood glucose level or free fatty acids [143]), hormonal disorders (e.g., insulin, leptin, estrogen [24,144,145]), chronic inflammation [22,24,146] with restricted immune competence [147], as well as alterations within the tumor microenvironment including increased desmoplasia and activation of PSCs [148].